Autacoids and respiratory system - Pharmacology for Medical Graduates, 4th Updated Edition

Histamine has no valid clinical use.

• 1.

  H ₁ -blockers cause CNS depression, sedation and drowsiness. Certain antihistamines have antiemetic, local anaesthetic and anti-parkinsonian effects.

• 2.

  They have antiallergic action; hence, most of the manifestations of type I reactions are suppressed.

• 3.

  They have anticholinergic actions – cause dryness of mouth, blurring of vision, constipation, urinary retention.

H ₁ -antihistamines are well absorbed after oral and parenteral administration. They are distributed widely throughout the body, metabolized extensively in liver and excreted in urine.

• 1.

  The common adverse effects are sedation, drowsiness, lack of concentration, headache, fatigue, weakness, lassitude, psychomotor incoordination, etc. Hence, H ₁ -antihistamines should be avoided while driving or operating machinery. These adverse effects are rare with second-generation antihistamines.

• 2.

  Gastrointestinal side effects are nausea, vomiting, loss of appetite and epigastric discomfort.

• 3.

  Anticholinergic side effects such as dryness of mouth, blurring of vision, constipation and urinary retention. These effects are not seen with second-generation antihistamines.

• 4.

  Teratogenic effects of some H ₁ -blockers have been observed in animals.

• 5.

  Allergic reactions may occur rarely with these agents, especially contact dermatitis on topical application.

• 1.

  Allergic diseases: H ₁ -antihistamines are used to prevent and treat symptoms of allergic reactions. For example, pruritus, urticaria, dermatitis, rhinitis, conjunctivitis and angioedema of lips respond to these drugs.

• 2.

  Common cold: They produce symptomatic relief by sedative and anticholinergic actions.

• 3.

  Preanaesthetic medication: Promethazine is used for its sedative and anticholinergic effects.

• 4.

  As antiemetic: Promethazine, diphenhydramine, dimenhydrinate, etc. are useful for prophylaxis of motion sickness because of their anticholinergic action. They act probably on the vestibular apparatus or cortex. Sedative effect also contributes to their beneficial effect. These drugs are useful in drug-induced and postoperative vomiting. Promethazine, in combination with other antiemetics, is used to control vomiting due to cancer chemotherapy and radiation therapy.

  

• 5.

  Parkinsonism: Imbalance between dopamine (DA) and acetylcholine (↓DA or ↑ACh) in the basal ganglia produces parkinsonism. Promethazine, diphenhydramine or orphenadrine are used to control tremor, rigidity (central action) and sialorrhoea of parkinsonism due to their anticholinergic and sedative properties. Promethazine and diphenhydramine are useful for the treatment of idiopathic and drug-induced parkinsonism.

• 6.

  H ₁ -blockers are used to control mild blood transfusion and saline infusion reactions (chills and rigors) and as adjunct in anaphylaxis.

• 7.

  Cinnarizine, dimenhydrinate and meclizine are effective for controlling vertigo in Meniere’s disease and other types of vertigo. Their antihistaminic and anticholinergic actions are useful in this condition.

• 8.

  Sedative and hypnotic: H ₁ -antihistamines (e.g. promethazine and diphenhydramine) are used to induce sleep, especially in children during minor surgical procedures.

Second-generation H ₁ -blockers are used in various allergic disorders, e.g. rhinitis, dermatitis, conjunctivitis, urticaria, eczema, drug and food allergies. For allergic rhinitis or hay fever, fexofenadine, cetirizine, mizolastine or rupatadine are used orally. Azelastine is used as nasal spray in allergic rhinitis. For urticaria, atopic dermatitis and other skin allergies, fexofenadine, cetirizine, mizolastine, loratadine and ebastine are useful. Azelastine and levocabastine are available as eye drops for allergic conjunctivitis.

• ■

  H ₁ -receptor and 5-HT _2A blocker

• ■

  Has sedative, antipruritic and anticholinergic effects

• ■

  Increases appetite

• ■

  Useful in carcinoid and postgastrectomy dumping syndrome (to control GI manifestations)

• ■

  Dry mouth, drowsiness, weight gain are some of the side effects

• ■

  5-HT _2A antagonist and α ₁ -blocker

• ■

  Has antihypertensive effect

They are 5-HT ₃ receptor antagonists used as antiemetics.

Clozapine, olanzapine, quetiapine, risperidone, etc. are 5-HT ₂ blockers used in schizophrenia.

• ■

  5-HT _2A/2C antagonist.

• ■

  It was used for prophylaxis of migraine.

• ■

  Long-term use causes abdominal and pulmonary fibrosis.

Ergot alkaloids occur naturally in a fungus, Claviceps purpurea . The most important compounds and their therapeutic uses are given in Table 6.3 .

Ergot alkaloids are contraindicated in ischaemic heart disease, hypertension, peripheral vascular disease and renal disease.

Prophylactic treatment may be required if migraine headaches occur two/three or more times in a month or if there is significant functional impairment during the attack. The drugs used are as follows:

• 1.

  B eta-blockers: Propranolol, timolol, atenolol, metoprolol, etc. Propranolol is more effective than other β-blockers; requires prolonged treatment. The mechanism of action is unknown.

• 2.

  Anti d epressants: TCAs like amitriptyline help to reduce attacks of migraine; exact mechanism of action of antimigraine effect is not clear. TCAs produce undesirable side effects on prolonged therapy.

• 3.

  C alcium channel blockers (CCBs): For example, verapamil and flunarizine. They reduce the frequency of attacks. Flunarizine is selective for cerebral calcium channels; it also has Na ⁺ channel–blocking effect. CCBs should not be co-administered with β-blockers.

• 4.

  A nticonvulsants: For example, gabapentin, sodium valproate and topiramate are used for migraine prophylaxis.

Others: Methysergide and cyproheptadine are rarely used for prophylaxis of migraine.

• 1.

  GI tract: PGE ₂ and PGI ₂ reduce acid secretion and increase the secretion of mucus in the stomach (cytoprotective action). Misoprostol (PGE ₁ analogue) is used for the prevention of NSAID-induced ulcers ( Table 6.4 ).

  

  Effects and uses of prostaglandins. Note: PGs – in the figure, actions/uses with plenty of ‘ P ’s and a single ‘ G ’.

  Table 6.4 ■

  Preparations, formulations and uses of prostaglandin analogues

  Preparations	Formulations/route	Uses
  • Dinoprostone (PGE 2 )	• Vaginal tab • Vaginal gel	• Induction of labour • Mid-term abortion • Termination of pregnancy
  • Dinoprost (PGF 2α )	Intra-amniotic injection	Mid-term abortion
  • Carboprost (15-methyl PGF 2α )	i.m.	• Mid-term abortion • Control of PPH
  • Gemeprost (PGE 1 )	Vaginal pessary	Cervical priming in early pregnancy
  • Alprostadil (PGE 1 )	• Intravenous infusion • Intracavernous injection	• To maintain the patency of ductus arteriosus in neonates with congenital heart disease until surgery • Erectile dysfunction
  • Misoprostol (PGE 1 )	Oral, vaginal pessary	• Peptic ulcer • Abortion, PPH
  • Epoprostenol (PGI 2 ) • Treprostinil (PGI 2 ) • Iloprost (PGI 2 )	Intravenous infusion	Pulmonary hypertension
  • Latanoprost (PGF 2α ) • Bimatoprost (PGF 2α ) • Unoprostone (PGF 2α ) • Travoprost (PGF 2α )	Topical (eye drops)	Glaucoma

• 2.

  Cardiovascular system: PGD ₂ , PGE ₂ and PGI ₂ cause vasodilatation. PGF _2α constricts pulmonary veins and arteries. TXA ₂ is a vasoconstrictor.

  • (a)

    PGE ₁ (alprostadil) is used to maintain the patency of ductus arteriosus before surgery.

  • (b)

    Prostacyclin (PGI ₂ ) decreases peripheral, pulmonary and coronary resistance. PGI ₂ (epoprostenol) is used to treat pulmonary hypertension. Other PGI ₂ analogues useful in this condition are treprostinil and iloprost.

• 3.

  Platelets: PGI ₂ inhibits platelet aggregation. Hence, it is useful during haemodialysis to prevent platelet aggregation.

• 4.

  Eye: PGF _2α has been found to decrease intraocular tension. Its analogues, e.g. latanoprost, bimatoprost, travoprost and unoprostone, are used in glaucoma.

• 5.

  Uterus:

  • (a)

    PGE ₂ (low concentration) and PGF _2α contract pregnant uterus; PGs are mainly used in mid-trimester abortion, missed abortion and in hydatidiform mole ( Table 6.4 ).

  • (b)

    Induction of labour: PGE ₂ and PGF _2α can induce labour at term.

  • (c)

    Cervical priming: PGE _2, PGE ₁ and PGF _2α promote ripening of the cervix; make the cervix favourable for induction and facilitation of labour.

  • (d)

    Postpartum haemorrhage (PPH): PGs increase tone as well as amplitude of uterine contractions. Carboprost (15-methyl PGF _2α ) can be used to control PPH.

• 6.

  Male reproductive system: PGE ₁ (alprostadil) is useful in the treatment of erectile dysfunction.

• 1.

  Abortion: PGs stimulate uterine contractions and cause ripening of the cervix.

  • ■

    Dinoprostone (vaginal) is used for induction of mid-trimester abortion, missed abortion and hydatidiform mole.

  • ■

    Misoprostol (oral or vaginal) can be used in combination with mifepristone or methotrexate to induce abortion in early pregnancy.

  • ■

    Carboprost (i.m.) is used to induce abortion in second trimester of pregnancy.

  • ■

    Gemeprost (PGE ₁ ) and dinoprost (PGF _2α ) are also useful for inducing abortion.

• 2.

  Induction of labour: PGs can be used to soften the cervix for induction of labour. PGE ₂ can facilitate labour by softening and dilatation of cervix.

• 3.

  PPH: Carboprost (i.m.) and misoprostol (oral) can be used to control PPH.

They are nausea, vomiting, diarrhoea, fever, flushing, hypotension and backache due to uterine contractions. Injections are painful due to sensitization of nerve endings.

(see p. 259)

Salicylate intoxication may be mild or severe. The mild form is called salicylism. The symptoms include headache, tinnitus, vertigo, confusion, nausea, vomiting, diarrhoea, sweating, hyperpnoea, electrolyte imbalance, etc. These symptoms are reversible on stoppage of therapy.

It is common in children. Manifestations are vomiting, dehydration, acid–base and electrolyte imbalances, hyperpnoea, restlessness, confusion, coma, convulsions, cardiovascular collapse, pulmonary oedema, hyperpyrexia and death.

Paracetamol is effective by oral and parenteral routes. It is well absorbed, widely distributed all over the body, metabolized in liver by sulphate and glucuronide conjugation. The metabolites are excreted in urine ( Table 6.7 ).

Acute paracetamol poisoning.

Acute overdosage mainly causes hepatotoxicity – the symptoms are nausea, vomiting, diarrhoea, abdominal pain, hypoglycaemia, hypotension, hypoprothrombinaemia, coma, etc. Death is usually due to hepatic necrosis.

Mechanism of toxicity and its treatment ( fig. 6.5 )

• ■

  The toxic metabolite of paracetamol is detoxified by conjugation with glutathione and gets eliminated.

• ■

  High doses of paracetamol cause depletion of glutathione levels. In the absence of glutathione, toxic metabolite (N-acetyl-p-benzo-quinoneimine [NAPQI]) binds covalently with proteins in the liver and kidney and causes necrosis.

• ■

  Alcoholics and premature infants are more prone to hepatotoxicity.

• ■

  N-acetylcysteine or oral methionine replenishes the glutathione stores of the liver and protects liver cells.

• ■

  Activated charcoal is administered to decrease the absorption of paracetamol from the gut.

• ■

  Haemodialysis may be required in cases with acute renal failure.

Mechanism of paracetamol toxicity and its treatment. NAPQI, N-acetyl-p-benzo-quinoneimine.

To relieve an acute attack, NSAIDs like naproxen, indomethacin, piroxicam, diclofenac, aceclofenac and etoricoxib are used. They are better tolerated than colchicine.

They inhibit active tubular reabsorption of uric acid in proximal tubules and increase excretion of uric acid, e.g. probenecid and sulphinpyrazone. They are rapid acting but poorly tolerated. High fluid intake is advised to prevent formation of urate crystals in urine. Sulphinpyrazone is an alternative to probenecid. Uricosuric drugs should not be given within 3 weeks of an acute attack of gout. They mobilize uric acid from tophaceous deposits, hence there is fluctuation in serum uric acid levels which can precipitate an acute attack. These drugs are contraindicated in patients with renal failure. Side effects are rare, but GI toxicity (nausea, vomiting) and skin rashes may occur.

They are excreted by active tubular secretion. When they are administered simultaneously, probenecid competes with penicillins/cephalosporins and blocks the tubular secretion of β-lactam antibiotics. Therefore, plasma levels of β-lactam antibiotics and their duration of action increases. Thus, the treatment becomes more effective.

They relieve symptoms as well as reduce disease activity in RA. The effects of DMARDs may take few weeks to several months to become evident. Once a diagnosis of RA is made, the patient should be started on a DMARD.

It is the preferred DMARD in the treatment of RA. It has relatively more rapid onset of action than other DMARDs. It is a folate antagonist. The dose of methotrexate used in RA is much lower than the dose needed in cancer chemotherapy. It exerts anti-inflammatory effect. It inhibits chemotaxis of neutrophils and decreases production of proinflammatory cytokines by activated T cells. Methotrexate is administered orally starting with a dose of 7.5–15 mg once weekly and increasing the dose by 2.5 mg weekly if there is no improvement. It can also be used in psoriasis, polymyositis, giant cell arteritis, dermatomyositis, etc.

These are antimalarial drugs – also useful in RA. The exact mechanism of action of these drugs in RA is not clear. They decrease release of lysosomal enzymes and scavenge free radicals. They are well tolerated. They are administered orally, highly bound to tissue proteins and deposited in melanin containing tissues, especially eye. Prolonged administration may cause corneal opacity and retinal damage. Hence, ophthalmologic examination should be done at least once a year in patients on chloroquine/hydroxychloroquine. The other side effects are nausea, vomiting and skin rashes. The drug is relatively safe in pregnancy. They are used alone in patients with mild disease or in combination with methotrexate and/or sulphasalazine.

It is used alone in mild disease or in combination with other drugs in severe cases. It causes remission in active RA and is also used for chronic inflammatory bowel disease. It is administered orally and is split in the gut by colonic bacteria. Common side effects are nausea, vomiting, diarrhoea, headache, skin rashes and leukopaenia.

Its active metabolite inhibits dihydroorotate dehydrogenase, thus decreases pyrimidine synthesis. It inhibits T-cell proliferation. L eflunomide is used alone or in combination with methotrexate for the treatment of RA. It is as effective as methotrexate. It is completely absorbed after oral administration and has a l ong plasma half-life of about 2–3 weeks. Hence, a l oading dose is given. Adverse effects include l oose stools (diarrhoea), l oss of hair, l iver toxicity (hepatotoxicity), l eukopaenia and skin rashes. It is contraindicated in children, in pregnant women and l actating mothers. ( Note ‘L’s. )

They are not used because of their toxicity.

It is a metabolite of penicillin and rarely used now because of toxicity.

Adverse effects are proteinuria, pruritus, pancytopaenia, pemphigus-like skin rashes, thrombocytopaenia and GI side effects.

Biologics are preparations made from microorganisms, animals or human or their products. They are administered parenterally. These agents are used in case of RA not responding to nonbiological agents. They are also useful in other autoimmune disorders like psoriasis, Crohn disease, ankylosing spondylitis and scleroderma ( Table 6.8 ).

Prolonged use may produce opportunistic infections like tuberculosis, P. jiroveci infection and urinary tract infection.

They inhibit cough reflex by suppressing the cough centre in medulla. They are used for symptomatic treatment of dry, unproductive cough. Antitussives should be avoided in children younger than 1 year.

• 1.

  Codeine:

  • (a)

    Has cough centre suppressant effect.

  • (b)

    Causes mild CNS depression, hence drowsiness can occur.

  • (c)

    Causes constipation by decreasing intestinal movements.

  • (d)

    Should be avoided in children and asthmatics.

    • Codeine is administered orally, has mild analgesic effect and less addiction liability than morphine.

• 2.

  Pholcodine: Antitussive action is similar to codeine. It has no analgesic or addiction liability. It is administered orally and has a long duration of action.

• 3.

  Noscapine: It is an opium alkaloid and has potent antitussive effect. It is useful in spasmodic cough. It has no analgesic effect, does not cause constipation, addiction or CNS depression. The side effects are nausea and headache; bronchospasm can occur in asthmatics.

• 4.

  Dextromethorphan: It is a centrally acting antitussive agent. It has no analgesic property, does not cause constipation and addiction; mucociliary function in respiratory passages is not affected. It may cause sedation and hallucinations.

• 5.

  Antihistamines: Diphenhydramine, chlorpheniramine, promethazine, etc. are useful in cough due to their sedative, antiallergic and anticholinergic actions. They produce symptomatic relief in cold and cough associated with allergic conditions of respiratory tract.

• 6.

  Prenoxdiazine: It acts peripherally on stretch receptors on the airways.

Syrups, lozenges, linctuses or liquorice may be used when cough arises due to irritation above the larynx. They increase salivation and produce protective soothing effect on the inflamed mucosa.

Syrup is a concentrated solution of sugar containing the drug to mask the bitter taste of the drug.

Lozenge, solid dosage form placed in the mouth and sucked; it dissolves slowly to liberate the active ingredient. It soothes the irritated mucosa of the throat, e.g. dyclonine (local anaesthetic) lozenge for sore throat.

Linctus, viscous liquid sipped slowly to allow it trickle down the throat; used for relief of cough, e.g. linctus codeine.

They increase the volume of bronchial secretion and decrease viscosity of the sputum; hence, cough becomes less tiring and productive. They include iodides, chlorides, bicarbonates, acetates, volatile oils, etc.

These agents break the thick tenacious sputum and lower the viscosity of sputum, so that sputum comes out easily with less effort.

These drugs competitively block the effects of cysteinyl leukotrienes (LTC ₄ and LTD ₄ ) on bronchial smooth muscle.

Thus, they produce bronchodilatation, suppress bronchial inflammation and decrease hyperreactivity. They are well absorbed after oral administration, highly bound to plasma proteins and metabolized extensively in the liver. They are effective for prophylactic treatment of mild asthma and moderate persistent asthma (in combination with other drugs). They are well tolerated, produce few adverse effects – headache, skin rashes and rarely eosinophilia.

Sodium cromoglycate (cromolyn sodium) and ketotifen are mast cell stabilizers. They are not bronchodilators. They inhibit the release of various mediators – histamine, LTs, PGs, PAF, etc. by stabilizing mast cell membrane ( Fig. 6.7 ). They also reduce bronchial hyperreactivity to some extent but the AG:AB reaction is not affected. Onset of action is slow.

Mechanism of action of mast cell stabilizers.

Sodium cromoglycate is not effective orally as it is poorly absorbed from the gut. In bronchial asthma, sodium cromoglycate is given by inhalation.

• 1.

  Systemic: Hydrocortisone, prednisolone, methylprednisolone and others.

• 2.

  Inhalational: Beclomethasone, budesonide, fluticasone and ciclesonide.

Glucocorticoids induce synthesis of ‘lipocortin’, which inhibits phospholipase A ₂ and thereby prevent the formation of various mediators such as PGs, TXA ₂ and SRS-A. Glucocorticoids have antiallergic, anti-inflammatory and immunosuppressant effects. They:

• 1.

  Suppress inflammatory response to AG:AB reaction.

• 2.

  Decrease mucosal oedema.

• 3.

  Reduce bronchial hyperreactivity.

Glucocorticoids do not have direct bronchodilating effect but they potentiate the effects of β ₂ -adrenergic agonists. They also prevent development of tolerance to β ₂ -adrenergic agonists.

Inhaled glucocorticoids such as beclomethasone, budesonide, fluticasone and ciclesonide are used as prophylactic agents in bronchial asthma. Inhaled glucocorticoids are used in patients with persistent asthma who require inhaled β ₂ -agonists frequently. Ciclesonide is a prodrug, gets activated by esterases in bronchial epithelium. They are well tolerated. Systemic side effects are minimal with these agents. The common side effects are hoarseness of voice, dysphonia and oropharyngeal candidiasis. These can be reduced by using a spacer, rinsing the mouth after each dose; oral thrush can be treated effectively by topical antifungal agent, nystatin or hamycin.

Combination of long-acting beta-agonist (LABA) with steroid is available, e.g. fluticasone + salmeterol; budesonide + formoterol. They have synergistic action; used in bronchial asthma and COPD. They are used in moderate and severe persistent asthma.

Systemic glucocorticoids are used in acute severe asthma and chronic severe asthma. Long-term use of systemic steroids produce severe side effects such as gastric irritation, Na ⁺ and water retention, hypertension, muscle weakness, osteoporosis and HPA axis suppression.

Omalizumab prevents the binding of IgE to mast cell, thus prevents mast cell degranulation. It has no effect on IgE already bound to mast cells. It is administered parenterally. It is used in moderate to severe asthma and allergic disorders such as nasal allergy and food allergy. It is approved for use in patients older than 12 years. It causes local side effects such as redness, stinging, itching and induration.